Hetero-Multivalent Targeted Liposomal Drug Delivery to Treat <i>Pseudomonas aeruginosa</i> Infections

Abstract

<i>Pseudomonas aeruginosa</i> is the leading nosocomial and community-acquired pathogen causing a plethora of acute and chronic infections. The Centers for Disease Control and Prevention has designated multidrug-resistant isolates of <i>P. aeruginosa</i> as a serious threat. A novel delivery vehicle capable of specifically targeting <i>P. aeruginosa</i>, and encapsulating antimicrobials, may address the challenges associated with these infections. We have developed hetero-multivalent targeted liposomes functionalized with host cell glycans to increase the delivery of antibiotics to the site of infection. Previously, we have demonstrated that compared with monovalent liposomes, these hetero-multivalent liposomes bind with higher affinity to <i>P. aeruginosa</i>. Here, compared with nontargeted liposomes, we have shown that greater numbers of targeted liposomes are found in the circulation, as well as at the site of <i>P. aeruginosa</i> (PAO1) infection in the thighs of CD-1 mice. No significant difference was found in the uptake of targeted, nontargeted, and PEGylated liposomes by J774.A1 macrophages. Ciprofloxacin-loaded liposomes were formulated and characterized for size, encapsulation, loading, and drug release. <i>In vitro</i> antimicrobial efficacy was assessed using CLSI broth microdilution assays and time-kill kinetics. Lastly, PAO1-inoculated mice treated with ciprofloxacin-loaded, hetero-multivalent targeted liposomes survived longer than mice treated with ciprofloxacin-loaded, monovalent targeted, or nontargeted liposomes and free ciprofloxacin. Thus, liposomes functionalized with host cell glycans target <i>P. aeruginosa</i> resulting in increased retention of the liposomes in the circulation, accumulation at the site of infection, and increased survival time in a mouse surgical site infection model. Consequently, this formulation strategy may improve outcomes in patients infected with <i>P. aeruginosa</i>.